A major problem in breast cancer treatment and the leading cause of mortality is invasion and metastasis of primary breast tumors. Very little is known about the fundamental biology of mammary tumors that can explain why certain tumors are aggressive in some individuals while relatively quiescent in others. The cell type from which the tumor arises may dictate its potential for invasion and metastasis. The mammary gland consists of different cell types including the cap cell; a less differentiated, highly proliferative cell basally located in the terminal end bud (TEB) of the murine mammary gland. The TEBs invade the fatty stroma of the pubertal gland establishing the ductal network. These specialized structures are reported to be targets for carcinogen- induced DNA damage. Their human counterparts are called intralobular ducts and are also sites of cancerous lesions. We hypothesize that genetic change specific to the cap cell population of the TEB will lead to aggressive tumors and metastatic disease. The long term goal of this research is to understand why some breast tumors are benign and others metastatic, and translate this information into better treatment protocols. P-cadherin is normally expressed in the cap cells of the TEB and its progenitors. The recent finding that P-cadherin expression in human breast tumors strongly correlates with poor patient survival suggests two possible explanations. Either P-cadherin expression is upregulated in transformed epithelial cells which normally do not express P-cadherin or these highly invasive tumors originate from a cap cell or stem cell-like progenitor. The experiments outlined in this proposal will directly examine the latter possibility. In order to determine the role of a specific subset of mammary cells in tumorigenesis we will generate an inducible expression system in which transgene expression can be tightly regulated in vivo. The endogenous P- cadherin promoter will be used to direct expression to the cap cells. The neu/HER-2 proto-oncogene will be induced in cap cells during specific periods of mammary gland development by administration of the tetracycline derivative, doxycycline. Tumor development will be examined in these animals and tumor pathology will be compared to human breast tumors as well as transgenic models. The goal of this research is to determine whether the highly proliferative and invasive cap cell population is a target for metastatic breast cancer.